One of the major physiological changes associated with aging is bone loss. The dynamic interaction between T cells and bone has been explored extensively in the context of rheumatoid arthritis and estrogen deficiency. However, the potential relationship between certain populations of clonally expanded memory CD8 T cells present in the elderly and bone homeostasis has never been investigated. The proposed interdisciplinary research will test the novel hypothesis that the process of replicative senescence in CD8 T cells exerts a deleterious effect on bone maintenance. Aging humans have a high proportion of CD8 T cells with features of replicative senescence, i.e., irreversible cell cycle arrest, permanent loss of CD28 gene expression, apoptosis resistance, reduced response to cellular stress, and shortened telomeres. Clinical studies have documented the correlation of high proportions of CD8 T cells bearing senescent markers with osteoporotic fractures in the elderly. Thus, senescent T cells, already documented to hinder immunity to infection in the elderly, may also play a role in age-related bone changes, via production of soluble factors. The T cell-mediated bone effects may be exacerbated by the age- associated increase in lipid oxidation products, which are known to activate T cells. The Specific Aims of this exploratory R21 research project are: (1) To analyze the effect of human CD8 T cell replicative senescence on osteoclasts and osteoblasts. A cell culture model, used extensively to dissect immune changes during aging, will be employed to compare early passage and senescent T cell effects on the in vitro generation and activation of osteoclasts and osteoblasts. The potential role of oxidized lipids in accelerating the progression of T cells to replicative senescence will also be explored. (2) To test whether T cells with the "senescent" phenotype present in elderly persons show similar characteristics to those identified in Aim 1 for T cells that are driven to replicative senescence in vitro. (3) To begin to address the potential role of dyslipidemia and oxidized lipids in chronic T cell activation-induced bone loss, using an in vivo mouse model of osteoporosis. The proposed studies, specifically linking memory T cell changes during aging with alterations in bone mass, will lead to novel therapeutic interventions that may simultaneously enhance both immune function and bone maintenance in the elderly.